The duration of MDR-TB treatment necessary to stop transmission is not known, but has great public health importance in South Africa and globally. Currently, most MDR patients are treated in hospital for the first 6 months, but only a small fraction of the estimated 500,000 annual new MDR TB cases are being treated and hospital capacity is one of several critical bottlenecks to the scale up. In South Africa an estimated shortage of almost 3,000 beds in 2008 has lead to long waits for admission in order to begin treatment, ironically leaving untreated patients waiting for beds in the community while hospital beds are occupied by patients on therapy who may well not be infectious. Preliminary retrospective observations in the Airborne Infections Research Facility in Mpumalanga province, South Africa, have suggested that MDR TB, like drug susceptible TB, may become rapidly non-infectious after as little as 24 to 72 hours on effective therapy. In this application we put fortha series of prospective experiments designed to measure infectiousness of MDR, pre-XDR, and XDR patients on conventional South African regimens for large numbers of sentinel guinea pigs in exposure chambers breathing the air exhausted from the adjacent 6-bed experimental TB ward. Transmission is determined by tuberculin skin testing the guinea pigs monthly. We will selectively admit a series of MDR, XDR, and finally pre-XDR patients as cohorts to the AIR facility for a series of 5 exposure experiments during which time they will receive conventional therapy for drug resistant disease per South African policy. They will receive 24 to 72 hours treatment before admission, as determined after the first experiment. We will measure several clinical and laboratory parameters of infectiousness to be sure that the cohorts are similar in factors other than drug resistance pattern. The end point will be the percentage of 90 exposed guinea pigs infected by each cohort. Relative infectiousness adjusted for person- days of exposure will be determined by statistical analysis. We hypothesize that standard South African MDR treatment will rapidly and profoundly stop transmission, but that in the absence of susceptibility to fluoroquinolones, transmission will be less well inhibited by the remaining drugs available for the tailored regimens in use in South Africa. PUBLIC HEALTH RELEVANCE: The duration of treatment needed to stop the person to person spread of highly drug resistant tuberculosis is not known. This information is critically important in South Africa and globally because such patients are usually treated in hospital for the first 6 months, leading to major shortages in hospital beds. Using a special experimental ward, this research project will directly measure the infectiousness of patients after just 24 to 7 hours of treatment, and if spread is as rapidly contained as preliminary studies suggest, the results will justify community based care rather than hospitalization in most cases.